Cancer
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart disease. In the year 2000, there were 553,091 cancer deaths in the US. In 2003, the American Cancer Society estimates that this number will increase to approximately 556,500, due to aging and growth of the population. Lung cancer is the most common fatal cancer in men (31%), followed by prostate cancer (10%), and colon & rectum cancer (10%). In women, lung (25%), breast (15%), and colon & rectum (11%) are the leading sites of cancer death. Among children, leukemia is the most common cancer among children ages 0-14 years and it comprises approximately 30% of all childhood cancers and accounts for the most childhood deaths. Acute lymphocytic cancer is the most common form of leukemia in children. It is estimated that 1.33 million new cases of cancer will be diagnosed in 2003 (American Cancer Society, 2003 Cancer Statistics Slide Set 2003).
In women, the incidence of breast cancer increases with age. 94% of new cases and 96% of deaths that were reported in the U.S. during 1996-2000 occurred in women who were 40 and over. It is estimated that more than 250,000 new cases of breast cancer will have been diagnosed in 2003, with approximate 200,000 diagnoses of invasive breast cancer. Among women in the United States, cancer of the ovary ranks fifth in incidence. There are no proven methods of prevention for ovarian cancer and it often is a rapidly fatal disease.
Current Treatments
Surgery, chemotherapy (CT) and radiation therapy (RT), and combinations thereof, remain the leading defenses against cancer, although recent advances in the field have led to widespread uses of specialized treatments such as angiogenesis inhibitors, biological therapies, including adjuvant therapy to boost the patient's immune system, antibody therapy, vaccine therapy, and photodynamic therapy. Radioimmunotherapy (RIT) is one such treatment which uses radioactively-conjugated monoclonal antibodies for both tumor localization by imaging, and for treatment. RIT is currently approved for the treatment of non-Hodgkin's lymphoma, and is being evaluated clinically for many tumor types, including malignant brain tumors.
However, CT and RT have numerous adverse effects. Patients undergoing CT may develop side effects including nausea, vomiting, diarrhea, hair loss, dry mouth and other oral complications, and cytopenia. For example, the main effect of paclitaxel (Taxol®) is red blood cell cytopenia due to effects on the bone marrow, however, it also causes allergic skin reactions, numbness in extremities, mouth sores, nausea, muscle and joint aches, vomiting, diarrhea, fatigue and hair loss. RT frequently causes anemia, skin irritation, temporary change in skin color in the treated area, temporary or permanent loss of hair in the area being treated, weight loss, fatigue, and hypoxic damage of normal tissue. Late toxic effects of radiation therapy, although uncommon, can include radiation pneumonitis, cardiac events, arm edema, brachial plexopathy, and the risk of second malignancies. Some chemotherapeutic drugs even have the very serious side effect of increasing the incidence of other types of cancer (Brown, Expert Opin Drug Saf. 2002; 1(3):253-67).
In addition to adverse effects of CT and RT, other limiting factors include development of drug resistance by the tumors, and induction of tumor cell growth arrest and senescence. While senescent tumors do not increase in size per se, they still retain the capacity to produce and secrete tumor stimulating mitogens and pro-angiogenic factors that can lead to tumor progression.
Accordingly, tumors continue to be difficult to treat with existing therapies. There is therefore a continued need in the art for non-toxic agents that can effect tumor cell killing and/or potentiate treatment with existing therapies, thereby allowing the use of lower effective doses of the toxic agents.
p-amino-benzoic-acid
para-amino-benzoic acid (hereinafter “PABA”), is a water-soluble naturally-occurring compound that is essential for microorganisms and some animals, but not humans. PABA is a component of pteroylglutamate, a form of folic acid, and is a co-factor for B-complex vitamins. PABA also appears to function as a co-enzyme in the conversion of certain chemical intermediates to purines.
PABA is a common ingredient in sunscreens due to its capacity to absorb ultraviolet radiation. PABA has also been used in clinical trials for the treatment of connective tissue diseases (e.g., scleroderma, dermatomyositis) and in combination with salicylates for the treatment of rheumatic fever. U.S. Pat. No. 6,368,598 suggested the use of PABA as a non-essential part of a linking group in a drug complex for the treatment of prostate cancers. In this complex, PABA functions as a leaving group that is separated from the cytotoxic therapeutic portion of the drug complex by the action of enzymes present at the site of the intended therapeutic action. PABA also has been shown to inhibit cell cycle arrest and DNA repair. The present inventors have also previously discovered that PABA inhibits melanogenesis in vitro and in vivo, alone or in combination with chemotherapy or radiation therapy (RT) (see U.S. provisional patent application No. 60/436,394-filed Dec. 24, 2002, and U.S. application Ser. No. 10/746,206 filed Dec. 23, 2003). PABA was also unexpectedly shown to inhibit the in vitro proliferation of Lewis Lung carcinoma cells, suggesting a melanin-independent mechanism of action.
Since other agents that inhibit cell cycle arrest and DNA repair have been shown to increase the efficacy of chemotherapy (Yu et al., Cancer Res 2002; 62:5743-5748; and Xiao et al., J. Biochem 2003; 278:21767-21773), it was hypothesized that PABA would have a similar effect.